Specifically, the long-term objective of the proposed research is to identify and characterize genes that are important in the pathogenesis of human parathyroid neoplasms (both adenomas and carcinomas). Although the majority of these genes have yet to be identified, genetic rearrangement and overexpression of a cell cycle regulator (PRAD1 or human cyclin D1) has been implicated in the pathogenesis of about 5% of parathyroid tumors. The underlying hypothesis for the proposed studies, then, is that abnormalities in other cell cycle regulators (p53, retinoblastoma (Rb) and cyclins other than PRAD1) and/or additional candidate oncogenes (some perhaps by their overexpression) are likely to be important in the pathogenesis of these tumors. To begin to test this hypothesis, human parathyroid adenomas will be examined for: (i) abnormalities in the p53 and Rb genes using "loss of heterozygosity" (LOH) studies and subsequent characterization of the remaining, non- deleted allele in tumors showing LOH; and (il) tumor-specific overexpression (or unique expression) of cDNAs isolated by subtractive hybridization, one or more of which may encode a putative oncogene or a gene functionally linked to an oncogene. These studies should provide important insights into the molecular mechanisms of tumorigenesis in these neoplasms, and could potentially have broader clinical and biological ramifications as has been the case for PRAD1).